DESCRIPTION (Applicant's abstract): The proposed research will examine the relationship between inherited tolerance to hypoxia and adaptive change in skeletal muscle biochemistry. Previous results have demonstrated that two loci of major effect are predominantly responsible for the hypoxia tolerant condition in mice, and an unknown number of modifying genes contribute to the response. Hypoxia tolerance is quantified here as the time to fatigue during treadmill exercise under hypoxic conditions (tet), and the adaptive condition is expressed in mice which have been acclimated to low PO2. Using two inbred strains of mice, their F1 hybrid, and subsequent backcross generations, it has been demonstrated that tet distributions segregate without overlap as expected for a simple two locus system. This means that treatment groups include the parentals and F1's of known genotype, and backcross manipuations where the variable genotype can be predicted without ambiguity based on the acclimatory response (tet). Skeletal muscle biochemistry and function is highly adaptable to altered conditions of energy supply or demand. Hypoxia presumably represents a disruption of a muscle cell's capacity for energy production. The present proposal will examine the adaptive responses in biochemical and structural aspects of muscle that relate to muscle energetics. Since the hypoxia tolerance genotype and its effect on hypoxia performance are known, the proposed experiments offer the possibility of making the link between genotype and phenotype. Genotype- and hypoxia- specific responses in muscle will be examined in high-energy phosphate compound maintenance, the creatine kinase enzyme system, and in the functional morphology of muscle. These tightly coupled lines of research are likely candidates for an energetic adaptation to hypoxia.